Exploring program death-1 and cytotoxic T lymphocyte antigen-4 safety in gastric cancer clinical trials: A meta-analysis

Background Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Despite advances in treatment options, the overall prognosis for advanced gastric cancer remains poor. Immunotherapy has revolutionized the field of cancer treatment by harnessing the patient’s immune system to target and destroy cancer cells. Two important immune checkpoint inhibitors that have shown promise in various malignancies, including gastric cancer, are program death-1 and cytotoxic T lymphocyte-4 inhibitors. Aims To assess and analyze the occurrence of adverse events associated with program death-1 and cytotoxic T lymphocyte antigen-4 in patients diagnosed with advanced gastric cancer. Methods Relevant studies were searched in reputable databases such as PubMed, Embase, Google Scholar, and the Cochrane Library from October 6, 2017, to February 3, 2022. Studies were analyzed with Review Manager 5.4. PROSPERO: CRD42023479662. Results Of the 500 studies retrieved, nine randomized control trials involving 5,185 patients were included in the meta-analysis comparing TRAEs in advanced gastric cancer patients after immune checkpoint inhibitor monotherapy and combined immune checkpoint inhibitors treatment. There was a lower risk of any grade of treatment-related adverse events with program death -1 than in the control arm (76.5% vs. 79%, P = 0.02). Program death-1 observed a lesser risk of grade 3-4 treatment-related adverse events as compared to the control for nausea (0.3% vs. 3%, P = 0.007) and fatigue (1% vs. 2.7%, P = 0.006). Program death-1 monotherapy also saw a decrease in the incidence of common treatment-related adverse events such as diarrhea (9.6% vs. 16%, P < 0.00001), nausea (6.8% vs. 20.6%, P < 0.00001) and fatigue (11% vs. 15.9%, P = 0.001). However, pruritus occurrence increased (3.8% vs. 9%, P < 0.001) after program death-1 compared to control. Conclusions Patients with advanced gastric cancer endured program death-1 treatment effectively. Nonetheless, the combination of program death-1 and cytotoxic T lymphocyte-4 results in a greater occurrence of treatment-related adverse events.


INTRODUCTION
2][3] The predominant histological type of GC is adenocarcinoma, making up around 85 to 90% of all cases. 4,5In developed nations, the likelihood of GC affecting males is significantly higher than that of females. 6GC can be classified into early and advanced stages based on disease progression, with early-stage cancer confined to the mucosa and submucosa, irrespective of tumor size or lymph node involvement.Middle-stage cancers extend into the muscle layer, while advanced-stage cancer occurs when tumor cells penetrate the subserosa or neighboring organs.Accurate staging of GC plays a critical role in determining the optimal treatment strategy. 7espite advancements in treatment over the past few decades, the prognosis for individuals with metastatic GC remains poor, with a median overall survival of less than a year, while patients with early-stage tumors may achieve a cure through surgery alone.Yet, those with advanced gastric cancer (AGC) have a limited lifespan of Exploring program death-1 and cytotoxic T lymphocyte antigen-4 safety in gastric cancer clinical trials close observation.In cases where the symptoms are moderate to severe, there may be significant morbidity and impairment of the nutritional and volume status, which may necessitate hospitalization and affect the patient's eligibility to receive further cancer treatment. 20The use of ICIs (CTLA-4 and PD-1 inhibitors) was linked to a higher risk of both all-grade and high-grade colitis, according to a previously published metaanalysis.Still, only 3 of the 10 randomized clinical trials (RCTs) used an anti-PD-1 antibody (nivolumab), while 7 out of RCTs used anti-CTLA-4 monoclonal antibodies. 26Therefore, it is unclear whether there is a risk of TRAEs for AGC following the application of ICIs.Currently, information regarding the toxicity of ICIs primarily comes from randomized controlled trials (RCTs), with limited data on the comparative risk of toxicities across various classes of these agents.To address this gap, we performed a meta-analysis to uncover the distinctions in treatment-related adverse events following the use of PD-1 and CTLA-4 inhibitors in RCTs involving patients with AGC.

MATERIALS AND METHODS
The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed in reporting this systematic review and meta-analysis. 27Since all analyses were based on previously published studies, no ethical approval nor patient permission was necessary.It was registered in PROSPERO, with registration number CRD42023479662.

Eligibility Criteria
The eligibility criteria were determined using the PICO framework. 28The research question focused on whether CTLA-4 and PD-L1 were safer during treatment in patients with GC.

Types of Studies
Randomized phase III trials reported in English were included in the meta-analysis.Literature that is not original, systematic reviews, meta-analyses, case reports, non-English papers, and animal studies were excluded.

Types of Participants
The meta-analysis included studies that involved patients diagnosed with gastrointestinal cancer or gastroesophageal junction cancer.

Types of Interventions
In the experimental arm, patients received PD-1 inhibitors alone and in combination with CTLA-4 inhibitors.The control arm comprised patients who received chemotherapy alone.

Comparisons
Studies comparing PD-1 and control, PD-1 in combination with CTLA-4 versus control were included.

Types of Outcomes
Studies that report TRAEs, including overall grade, common grade, and grade 3-4, were included in the meta-analysis.Literature lacking sufficient data was excluded from the study analysis.

Search Strategy
Renowned four databases, PubMed, Google Scholar, Embase, and the Cochrane Library, were searched for important clinical trials.The data included in the meta-analysis was from October 6, 2017, to February 3, 2022.The search terms used are shown in Table 1.The search was limited to RCTs published in the English language.The study was conducted per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. 29

Data Extraction and Quality Assessment
Data was independently extracted from selected literature, and any discrepancies were resolved through mutual agreement.Information such as author name, year, trial type, clinical trial number, tumor type, study design, phase, and the number of patients were documented as presented in Table 2. Treatment types such as PD-1 (nivolumab, pembrolizumab, avelumab, CTLA-4 (ipilimumab), and chemotherapy, patient age in years were recorded, and outcomes including TRAEs (any grade, grade 3-4, and common grade were also Exploring program death-1 and cytotoxic T lymphocyte antigen-4 safety in gastric cancer clinical trials collected), as seen in Table 3.This study used the Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1 risk of bias tool to independently assess the trials' quality. 30Sequence generation, allocation concealment, blinding, incomplete data, selective reporting, and other sources of bias were assessed.The term "high risk" was used to describe a trial with a high risk of bias in one or more important domains.A trial was deemed "low risk" if it had a low bias risk across all critical domains.If not, it was determined "unclear," as shown in Figures 1A and B. Differences between the researchers were resolved through discussion.The risk of biased studies is shown in Table 4.

Statistical Analysis
Utilizing the Cochrane Collaboration's Review Manager (RevMan) software, version 5.4, statistical analysis was carried out.The odds ratio (OR) with a 95% confidence interval was used to pool dichotomous variables.Heterogeneity between studies was assessed using the consistency statistic (I 2 ).Heterogeneity among studies was evaluated using the inconsistency statistic (I ).If I was < 50%, the eligible studies were considered homogenous; hence, the fixed effect model was used.
In contrast, if I was > 50%, the pooled results were said to be significant and heterogeneous, and the random effect model was used instead.
The study used a fixed-effect model with the Mantel-Haenszel method to calculate the outcome, assuming no differences were observed among the studies.If there was substantial heterogeneity, a random-effect model was used instead-a p-value of less than 0.05 determined statistical significance.

The Patients' Characteristics
A total of 500 potential trials with PD-1 and CTLA-4 were identified, of which 80 were thoroughly examined.Finally, nine articles were included in the meta-analysis, including 5,185 patients diagnosed with GC, as shown in Figure 2.Among these patients, 2,175 were administered PD-1, and 1,559 were controls.Also, 728 patients received PD-1 in combination with CTLA-4, and 713 acted as control.The characteristics of the included studies are summarized in Table 2.All the trials were in phase shown in Figure 3A.7,39 PD-1 (24%) treatment showed a lower risk of grade 3-4 TRAEs compared to the control (33%) (OR: 0.70 95% CI [0.59-0.83]and P < 0.001), as seen in Figure 3B.

Any-Grade (PD-1+CTLA-4 versus Control)
In this analysis, two studies focused on examining the use of PD-1 in combination with CTLA-4 versus the control group. 34,38The results revealed that the risk of any grade treatment-related adverse TRAEs was significantly lower in the control group than in the combination group (62.5% vs. 79.5%)(OR: 2.32 95% CI [1.84-2.94]and P < 0.00001) as shown in (Figure 6A).

Publication Bias
Figure 7 depicts the pruritus funnel plot.No evidence of publication bias was found because all studies fell within the 95% CI range.The Egger test was run to offer statistical support for the symmetry of the funnel plot.The results still did not show any proof of publication bias in pruritus (OR: 2.45 95% CI [1.57-3.83]and P < 0.0001).

DISCUSSION
The TRAEs following PD-1 and CTLA-4 therapy for AGC have not yet been sufficiently assessed.These TRAEs after PD-1 and CTLA-4 therapy for patients with were the focus of 9 RCTs involving 5,185 patients, as reported in this meta-analysis.The findings from the current meta-analysis indicate that the risk of experiencing any grade and grade 3-4 adverse events were higher in the control group compared to PD-1, with percentages of 76.5% versus 79% (P = 0.02) and 24% versus 33% (P < 0.001), respectively.Another meta-analysis found that 11.3% of patients who received anti-PD-1 therapy for AGC Exploring program death-1 and cytotoxic T lymphocyte antigen-4 safety in gastric cancer clinical trials experienced at least one grade 3 adverse event and that nearly 50.8% of patients had at least one any-grade TRAE. 41In this study, the most frequently reported TRAEs were diarrhea (9.6% vs. 16%, P < 0.00001), nausea (6.8% vs. 20.6%,P < 0.00001), and fatigue (11% vs. 15.9%,P = 0.001).After receiving PD-1 treatment, there was a reduced risk of experiencing diarrhea, nausea, and fatigue.However, the control group exhibited a lower pruritus incidence than the PD-1 group.Additionally, common grade 3-4 adverse events included diarrhea (9 patients vs. 23 patients, P = 0.004), nausea (0.3% vs. 3%, P = 0.007), and fatigue (1% vs. 2.7%, P = 0.006).PD-1 therapy showed a decrease in the occurrence of these common grade 3-4 adverse events as compared to the control group.The study conducted by Chen et al. reported an incidence of grade 3 TRAEs at 14.6%.Furthermore, the overall incidence of ICI-related TRAEs was reported to be 56.8%. 42The most prevalent TRAEs in patients receiving ICI treatment were fatigue (14.1%), pruritus (10.3%), rash (9.8%), diarrhea (8.2%), hypothyroidism (7.0%), decreased appetite (6.1%), nausea (5.7%), and anemia (4.4%). 42Additionally, another metaanalysis identified TRAEs such as pruritus, diarrhea, rash, fatigue, decreased appetite, nausea, malaise, hypothyroidism, pyrexia, colitis, and anemia.The study did not observe any noticeable difference between the control group and PD-1 therapy concerning these adverse events. 43According to Abdel-Rahman et al., patients taking PD-1 and CTLA-4 inhibitors are more likely to develop colitis and diarrhea of all grades, as well as high grades of diarrhea. 44In the study findings, patients treated with a combination of PD-1 and CTLA-4 exhibited a higher incidence of any grade of TRAEs compared to the control group (35% vs. 40%, P = 0.04).These results are consistent with a trial involving AK104 (PD-1/CTLA-4), where 79.4% of patients reported TRAEs and 29.4% experienced grade 3 TRAEs. 45Siwei Pan and colleagues also observed that while the anti-PD-1 plus anti-CTLA-4 treatment (32.000%) was worse, the anti-PD-1 drug (64.5%)avoided severe TRAEs better than chemotherapy or placebo. 46Immune-mediated side effects were as frequent as one might expect with this combination and were the main outcome of nivolumab plus ipilimumab therapy. 45Additionally, a previous study found that when nivolumab and ipilimumab were combined, the incidence of gastrointestinal adverse events in all grades significantly increased, supporting our study's findings. 47The aforementioned results from studies emphasize the importance of careful evaluation when administering a combination of ICIs to patients with AGC.In this meta-analysis, some limitations were taken into account.Few clinical trials are available to assess the TRAEs of ICIs properly.Second, the dosage of ICIs and type of chemotherapy used in each included study varied, which may impact how we interpret our findings.Third, ethnic variations were not assessed in this study.Despite their limitations, the estimates of the safety of ICI inhibitors in the treatment of AGC patients are meaningfully studied in this meta-analysis.To overcome this boundary, an increase in the number of clinical trials should be conducted, standardized dosages of chemotherapy and ICI protocols should be established, and finally, future studies should include an assessment of ethnic factors to understand the impact of ICIs in different populations.By implementing these strategies, future studies and meta-analyses can improve the evaluation of the safety and effectiveness of ICIs in the treatment of AGC and provide more robust evidence-based recommendations.

CONCLUSION
In summary, the study indicates that program death-1 monotherapy demonstrates good tolerability in patients with advanced gastric cancer.However, combining program death-1 and cytotoxic T lymphocyte-4 increases the risk of treatment-related adverse events of any grade.Additionally, the use of chemotherapy regimens elevates the risk of treatment-related adverse events in advanced gastric cancer patients.Future trials are necessary to verify the impact of dosage reduction on treatment-related adverse events to improve patient prognosis.

Figure 1 .
Figure 1.(A) Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.(B) Risk of bias summary: review authors' judgments about each risk of bias item for each included study.

Identification Screening Included Eligibility Figure 2. Prisma flow diagram.
VOL. 2024 / ART.31Exploring program death-1 and cytotoxic T lymphocyte antigen-4 safety in gastric cancer clinical trials